Anaesthetic composition



RM May 14, 1935 UNITED STATES PATENT ori ce oal Mfg. Co.

Inc., Brooklyn,

N. Y., a corporation of New York No Drawing.

Original No.

1,924,685, dated Allllllt 29, 1933, Serial No. 500,671, December 6, 1980. Application for reissue December 1934, Serial No. 757,530-

10 Claims. rev-{m This invention relates to substances and particularly anaesthetic solutions for hypodermic injection and processes for producing the same. It is known that the hypodermic injection of acidcontaining substances of this type often causes as an after-effect considerable pain and swelling at and around the place where the injection was made. I have found that this is due almost entirely to the compositions and properties of the liquid used. I have also found that such solutions have sometimes a delayed action due also in large part to the character of the solution.

The principal object of the invention accordingly is to provide a composition for local anaesthesis, which shall do away with or substantially lessen the pain, swelling and other objectionable symptoms resulting from hypodermic injection thereof while accelerating at least to some extent the anesthetic eflect desired; another object is to provide a simple process for producing such composition.

The invention accordingly comprises the novel compositions and component mixtures comprised in such compositions, as well as the novel processes and steps of processes according to which such compositions may be manufactured, speciilc embodiments of which are described hereinafter by way of example only and in accordance with what I now consider the preferred manner of practicing the invention.

It has been discovered that when a highly acid material having a hydrogen ion concentration of pH l-Z is injected into the tissues there s rapid buffering of the acid or neutralization thereof by the reserve alkali of the body (carbonates and phosphates) which are called upon to effect this neutralization. This rapid buffering occurs at the point of injection to protect the tissues there from complete destruction. The resultant buffering simply limits the area where the destruction of tissue occurs, but destruction of the tissue within the area proceeds. I have discovered that with acid solutions of lower acid concentration such as those of pH 3-4, upon injection thereof into the tissues there is no immediate neutralization by the body alkalies. In fact the buffering action of the alkalies is so slow that the sloughing destruction or irritation of tissue may occur over alarge area. 7 Highly acid solutions also have the known property of readily dissolving and preserving from oxidation easily decomposable substances such as epinephrim On the other hand such highly acid solutions are apt to produce considerable toxicity and in addition I have observed an objectionable specific effect of high acid con-' centrations when used with anaesthetic solutions containing epinephrin. The observation that I have made is that when the highly acid solution is injected there is an absorption of the epinephrin through the capillaries which are swelled by the acid and so distributed to the body fluids, After the acidity has been neutralized these capillaries .will contract and then and only then will the vaso constricting action of the epinephrin become effective. It is that interval in which the capillaries have become enlarged and carry the epinephrin into the blood stream which causes toxic disturbance. Delay in anaesthesia, especially in the case of nerve blocking is directly attributable to this cause, in turn brought about by the highly acid solution.

I have found accordingly that with a less acid solution and particularly a solution which has a pH of 5.7 or over (the approximate critical acid value of blood) the objections mentioned above are substantially avoided. I have found it important to modify the less acid solutions in order on the one hand to secure a proper buffering or neutralizing effect and on the other hand to dissolve and avoid decomposition of the substance epinephrin. I have also found that with these less acid solutions the rate of diffusion may be increased by using solutions having a higher density than have heretofore been in use.

In accordance with my invention I have thus found that objectionable effects of solutions heretofore employed may be' overcome or substantially lessened by suitable regulation of the acidity or pH contentand of the density of the material, suitable buffering agents being employed, and when epinephrin or the like is used a suitable solvent and agent for preventing decomposition thereof being used.

As mentioned above my research has indicated that when a solution is used which has a pH of 5.7 or over-the critical acid value of bloodresults in accordance with my invention are obtained. The pH of blood is about 7.4. A solution with apH approximating that of blood or accordingly about neutral I have found gives better results than one just above the critical acid value. I prefer to use a solution having an acid value of pH 6.4 approximately. I have found that with such solutions the density should be incific gravity I find are inter-dependent. Solutions of high speciflc gravity and low pH number do not appearto function properly while solutions of high pH numberv and low specific gravity also appear to function improperly.

Instead of the high acid concentrations to prevent the decomposition of epinephrin or similar substances, I have found that I may preserve this material by the use of sodium bisulflte or equivalent anti-oxidizing agent having a low acidity,

and compatible with the body fluids and with the other ingredients of the composition set forth below. With the use of this material I-flnd that epinephrin, which will ordinarily in a few hours exposure to the sunlight in a solution where the hydrogen ion concentration is about 6.4, is substantially as well preserved as in more highly acid solutions now in As pointed out above it is important to buffer the solution with salts which are compatible with body fluids and with epinephrin where'used at the hydrogen ion concentration selected. I prefer to employ a phosphate such as an alkali acid phosphate as one of the buffering components .since this material approximates in its action more nearly the buflering'action. of the. normal body fluids. I prefer. di-sodium phosphate and potassium di-hydrogen phosphate as the buffer in connection with the composition for local anus- ;thesia. With this material I also employ sodium chloride to help attain a more nearly isotonic solution.

As a preferred formula which has been successfully used for local anesthesia, I employ the following:-20 grams of procainehydrochloride,

.022 gram molar di-sodium phosphate. .005

gram molar di-hydrogen potassium phosphate, .1 molar gram sodium chloride, .025 molar gram sodium bisulflte, 2 c. c. of N/ 1000 phosphoric acid 'and .052 gram of epinephrin were combinedwith sufficient water to make one liter.

The solution so made up has a specific gravity of approximately 1.0110 and a pH value of 6.4.

At about this pH value, namely approximating When tested clinically it has been found to produce anesthesia rapidly the necrosis swelling and after-pain practically disappear, toxic symptoms are substantially absent and the recovery from the'eifect of the local anesthesia is practically uneventful.

It is to be understood that other materials may be substituted for those in the formula given above, as long as the hydrogen ion concentration is maintained at or near the preferred pH value given. I find that a satisfactory range of operation of pH values is from about 5.7 to 8.0. With this pH value a specific gravity of 1.0110 and above should be employed. Instead of the phosphates mentioned in the formula, acetates, tartrates, carbonates and citrates may be employed. The following represent combinations which have been used to replace the mixture of di-sodium phosphate and di-bydrogen potassium phosphate,

and to regulate the acidity. appearing in the preferred formula:

1. Sodium and potassium tartrates buffered with tartaric acid; a

- 2. Sodium, calcium and potassium acetate buffered with acetic acid;

3. Sodium and potassium citrate with caustic soda and hydrochloric acid;

4. Citric acid with di-sodium. phosphate; 5,. Mono-, di-, and tri-sodium phosphate, the

mono-sodium phosphate being used to modify the alkalinity of the dior tri-s odium phosphate with potassium acid phosphate and phosphoric acid;

6. Carbonates of sodium and potassium with hydrochloric acid;

7. Other substances buffered to give a pH range from 5.7 to 8.0 may be employed.

Instead of the hydrochloric acid salt of procaine, other acid salts thereof such as the nitrate and the sulfate maybe used.

The term buffer as employed in the claims below refers to a salt like disodium phosphateor other salts mentioned herein, which upon being put into water solution dissociates and produces a small amount of weak acid and alkali. A general definition of buffer salts as given in General Chemistry by Horace G. Deming, pub. by John Wiley & Sons, 1923, page 250, is:-Salts which tend to hold the hydrogen or hydroxyl concentration of a solution to a definite value are called buffer salts. Acid solutions are buffered with salts ofinactive acids (sodium acetate or disodium phosphate), basic solutions by salts of inactive bases (ammonium chloride). 7

While I have described my improvements in great detail and with respect to preferred forms thereof, I do not desire to be limited to such details and forms since many changes and modiflcations may be made and the invention embodied in widely different forms without departing from the spirit and scope thereof in its broader aspects. Hence I desire to cover all modifications, forms and embodiments coming within the language or scope of any one or more of the appended claims.

, What I claim as new and desire to secure by Letters Patent, is:

1. An anaesthetic solution for hypodermic in-' constricting material and a buifer including a weak acid to dissolve and maintain said vasoconstricting material in solution and to modify the pH of the solution, said solution being substantially stable and having a pH value in a range from approximately 5.7 up to approximately neutral. v

2. An anaesthetic solution for hypodermic injection containing a solvent, an acid salt annsthetic material for local anaesthesia, a vaso-constricting material, a buffer including a buffer salt,

buffer ingredients being in proportion such that th'epflvalueoithesomtionisinarangeoi'apthatoithecriticalacidvalue oithe blood up to approximately neutral.

4. an amthetic solution ranging from slightly acid to nearly neutral containing an anmthetlc acid salt for local anathesia, a bufler, a vasoeonatricting material, a weak acid to dissolve the vase-constricting material and an anti-oxidant.

I. An amthetic solution ranging from slightly acid to nearly neutral containing an anaesthetic acid salt for local anasthesia, an alkaline butler, epinephrin, a weak acid to dissolve said epinephrin selected from the group acetic acid, tartaric acid. citric acid and phosphoric acid j and an anti-oxidant. I

I. an anesthetic solution for hypodermic inioctim, containing a solvent, procaine in m form of the usual hydrochloric acid salt, epinephrin, abuilermaterial eontaininganalkalinesaltto reduce the acidity due to the procaine hydrochloride. an anti-oxidising agent for preventing oaidatimottheeplnephrimthesolutionhavlngapH value somewhatlower than that of blood but appreciablyhigherthanthatoiacorrespondingl7 concentrated solution of said procaine hydrochloride, said solution being mbstantially stable.

7. an anesthetic solution ior hypodermic inJection.containlnlasolvont,procalneinthe iormot the usual hydrochloric acid salt. epineph'rin, a butler material containing a salt. and an antioaidiling agcnt'ior preventing oxidation of the epinephrin. the proportion of the ingredients be- \ingsuchthatthepflvalueoithesolutionisequal to about 6.4 and'the specific gravity thereof is about 1.0110 or more, said solution being Ill stantially stable.

8. An anesthetic solution for hypodermic injection containing procaine, di-sodium phosphate, di-hydrogen potassium phosphate, sodium chloride, sodium bisulflte, phosphoric acid, epinephrln and water, the proportion oi the ingredients being such that the pH value of the solution is approximately 6.4.

9. A base composition iormaklng a substantially stable anesthetic solution for hypodermic inJection, including acid-containing anzsthetic material for local anesthesia and a boiler material containing a salt for altering the pH of the base when in solution, a vase-constricting material and an anti-oxidant material, said base when placed in water being adapted to produce an anmsthetlc solution having a pH value within a range from approximately that 0! the critical acid value of blood up to that of the blood itself.

10. A base composition for making a substantially stable anaesthetic solution for hypodermic injection containing procaine hydrochloride, epinephrin, an alkaline di-sulilte, a buffer material containing a phosphate, and a weak acid, in proportions such that when placed in water to make an anesthetic solution such'solution will have a pH value in a range from approximately that of the critical acid value of the blood up to approximately that of the blood itself.

AMUEL n. aonnnm. 

